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Toxcast Chemical and Bioactivity Profiles for In Vitro Targets in the Retinoid Signaling System (SOT)
Citation:
Baker, N., S. Hunter, J. Franzosa, A. Richard, R. Judson, AND T. Knudsen. Toxcast Chemical and Bioactivity Profiles for In Vitro Targets in the Retinoid Signaling System (SOT). Presented at 2016 SOT Annual Meeting, New Orleans, LA, March 13 - 17, 2016. https://doi.org/10.23645/epacomptox.5173810
Impact/Purpose:
Poster presentation at SOT 2016 annual meeting.
Description:
A predictive model for prenatal developmental toxicity using ToxCast Phase I showed the RAR assay set to be the strongest weighting factor (Sipes et al. 2011). Retinoid signaling mediates growth and differentiation of the embryo. ToxCast has 6 reporter assays for trans-activation of retinoic acid receptors (RARa, RARb, RARg, and RXRa, RXRb, RXRg) and cis-activation of DR5 response elements by RAR/RXR, yielding a total of 879 ToxCast AC50s (conc. 50% effect) mapped to molecular targets in the retinoid system. In total, 97 of 1858 chemicals (5.2%) hit ≥one assays in the retinoid system at an AC50 below 2 uM. Several persistent organochlorines activated the RAR system at AC50s below 2 uM; several organotins and tert-butyl compounds activated the RXR system below 0.2 uM and 2 uM, respectively. All-trans retinoic acid was the most potent chemical tested in the RARa (AC50 = 0.43 nM) and RXRa (AC50 = 0.31 nM) trans-activation assays, and closely followed several tributyltin compounds as the most potent on the DR5 (AC50 = 6.26 nM) assay. A subset of 263 chemicals was tested on mouse embryonic stem cell (mESC) differentiation and cytotoxicity. In all 54% of the subset showed effects on mESC, including 58% of the DR5 compounds, 63% of hCYP1A1 compounds and 81% of RAR/RXR compounds. A preliminary analysis with the devTOXquickPredict (Stemina) ESC assay revealed a weak correlation with chemicals active on the RAR/RXR/DR5 system and a targeted biomarker response (ORN/CYSS ratio) that is ~84% predictive for teratogenicity in a human system. In conclusion, in vitro profiling of retinoid signaling identified ~ 5% of ToxCast chemicals with a potential for disruption of retinoic acid signaling through trans-activation of RAR or RXR at submicromolar concentrations. The potential for RAR and RXR to heterodimerize with different nuclear receptor families suggests these compounds may potentially disrupt multiple signaling pathways. This abstract does not reflect EPA policy.
URLs/Downloads:
DOI: Toxcast Chemical and Bioactivity Profiles for In Vitro Targets in the Retinoid Signaling System (SOT)
BAKER_SOT_2016_TBK_NCB FINAL.PDF (PDF, NA pp, 732.089 KB, about PDF)
TBK_RETINOID_SOT2016_SH_NCB KMC_FINAL.PDF (PDF, NA pp, 110.094 KB, about PDF)